Nourishment-improving feedstuff additives are an indispensable component of animal nutrition today. They serve for a better utilization of the food offered, stimulate growth and promote protein formation. One of the most important of these additives is the essential amino acid methionine, which is quite important as adjuvant especially in the raising of poultry. However, so-called methionine substitutes are becoming increasingly significant in this area since they have growth-stimulating properties similar to those of amino acids known for such properties.
Among these substitutes 2-hydroxy-4-(methylthio)-butyric acid is known as methionine-hydroxy analogue, abbreviated MHA, in racemic form as additive and has become economically significant.
MHA is obtained and used in the form of aqueous solutions with active-substance contents between approximately 88-90%. However, these concentrates contain not only the monomeric acid but also, as a consequence of inner-molecular esterification, oligomers, primarily linear and cyclic dimers as well as, to a lesser extent, tri- and tetramers. It is desirable on account of the known, lower nutritive efficiency of action and the poorer rheological behavior to keep the oligomer content as low as possible. On the other hand, the formation of oligomers is subject, as are all .alpha.-hydroxy acids, to the laws of chemical equilibrium and their amount can therefore not be freely selected. Rather, it is a function of the parameters such as concentration, temperature, pH and water content which determine the adjustment of the equilibrium. It is possible to obtain products with a distinctly lower oligomer portion than corresponds to the equilibrium due to the inertia of the equilibration reaction under suitable conditions; the ratio of monomers to the sum of the oligomers is then usually above 4:1 and can even reach values above 5:1. However, the ratio constantly shifts after a fairly long storage in favor of the oligomers until finally, after the adjustment of equilibrium has been completed, the monomer portion has dropped to approximately 2.5 to approximately 3:1 as a function of the water content, temperature and pH. The product "ages".
This ageing process also constitutes an application-specific disadvantage of commercial MHA.
Another production-specific disadvantage is the compulsory accumulation of inorganic ammonium salts associated with the obtention of MHA. Thus, in the production process customary today in the art approximately the same amount of ammonium sulfates are produced per kg MHA as waste-water ballast (see below). However, their removal or workup for being utilized elsewhere is associated with additional expense which makes the process and therewith the target product considerably more expensive.
The methionine substitutes also include certain salt-like compounds of MHA such as, in particular, its calcium salt and mixed calcium ammonium salt. However, they have not achieved the same commercial significance as the free acid, since their production is associated with higher production costs. In addition, they can not be added as simply and homogeneously as powdery, slightly hygroscopic solids into the feedstuff mixtures as the readily sprayable, aqueous concentrates of the free acid.
A further additive of this substance class is ammonium-2-hydroxy-4-(methylthio)-n-butyrate, abbreviated MHAAS. Although it has been known for a rather long time, MHAAS has not been accepted as yet in animal nutrition. This is probably connected in particular with the fact that the salt in its pure form can be isolated only with difficulty and with considerable expense and is obtained either as a viscous oil or as a deliquescent and hygroscopic mass. Also, the handling of such a substance which tends toward inhomogeneity poses problems in the area of application technology, for which reason it is difficult to exactly determine its biological merit. In any case, there has as yet been no secure knowledge about its nutritive equivalence in relation to current market products.
2-hydroxy-4-(methylthio)-n-butyramide, abbreviated MHA amide, is also known as a methionine substitute. However, the purposeful production of the compound, which occurs as intermediate stage in the MHA process, and the separation from the hydrolysis mixtures turn out to be very difficult. Low yields of crystalline MHA amide as well as its nutritive efficiency, which is less compared to that of MHA itself, are also reasons why this substance has remained insignificant commercially.
The general process for producing MHA and its alkaline/alkaline-earth salts starts with 3-methylmercaptoproprionaldehyde, also designated as MMP, which is nitrilized with hydrogen cyanide to 2-hydroxy-4-methylthio-butyronitrile, also designated as MMP-cyanohydrin or MMP-CH (equation I). ##STR1##
The MMP-cyanohydrin produced is then hydrolyzed customarily with strong mineral acids such as H.sub.2 SO.sub.4 or HCl via the intermediate stage of 2-hydroxy-4-methylthiobutyramide, also designated as MHA, (equation II), ##STR2##
to the methionine hydroxy analogue (MHA) (equation III). ##STR3##
This hydrolysis can be carried out in one stage or in two. In order to arrive at the MHA salt the MHA present in the product mixture is treated in a suitable manner either directly or after previous isolation.
Such different separating techniques as solvent extraction, salting out, precipitation, filtration and concentration can be used for the isolation either individually or in combination.
The MHA acid present can be further processed to the desired MHA salt e.g. by being treated with metal oxides, -hydroxides, -carbonates. In order to arrive at the ammonium salt (MHAAS) MHA can be treated e.g. with ammonia (equation IV): ##STR4##
In any case, an important problem is to separate the particular target product from the inorganic accompanying substances and ballast substances, whose workup along with their utilization and removal presents a significant problem according to today's standards and can decisively influence the economy of the basic production process.
A great number of processes are described in the patent literature which have as their subject matter the obtention of MHA as such and also that of the alkaline/alkaline-earth salts, preferably of calcium- and mixed calcium ammonium salts.
The processes of European patents EP 142,488; 143,100; 330,521 and those of American publications U.S. Pat. Nos. 3,773,927 and 4,353,924 concern the production of MHA in the form of aqueous concentrates.
A two-stage hydrolysis starting from MMP-CH forms the basis of the processes of EP patent 142,488 (with sulfuric acid) and of EP patent 143,100 (with mineral acid). Cyanohydrine is hydrated therein at first at relatively low tepperatures with e.g. 50-70% sulfuric acid to MHA amide, whereafter the hydrolysis is completed at higher temperatures after dilution with water. Then the reaction mixture is decomposed by extraction, making use of certain solvents partially mixcible with water. MHA is then obtained from the organic extract in cncentrated, aqueous solution by evaporating the solvent under determined conditions in the presence of water. In this manner a high-quality end product is obtained at first in very good yield which is distinguished in particular by little discoloration and a relatively low oligomer portion which is clearly below that of the equilibrium composition. A disadvantage of this process is the problematic nature of the ammonium bisulfate separated in the aqueous raffinate as coupled product, about whose whereabouts and/or removal no data is presented and which results if untreated in a considerable waste-water pollution load which can hardly be justified. The previously mentioned ageing tendency of the monomer/oligomer concentrates obtained which are comparatively low in the fresh state but in any case below the equilibrium ratio is also a disadvantage in this process.
MHA concentrates without the aid of a solvent are obtained according to U.S. Pat. No. 3,773,927 by a two-stage hydrolysis of MMP-CH with hydrochloric acid, subsequent concentration of the reaction mixture along with separation of the crystallized ammonium chloride. However, the MHA obtained in this manner is heavily discolored and rich in oligomers. The ammonium salt isolated as coproduct is also contaminated, so that it has no chance of being utilized and is therefore to be regarded as a worthless ballast substance.
An improvement of the previously cited process is achieved in U.S. Pat. No. 4,353,924 in that the excess mineral acid is neutralized with ammonia or other alkalinely reacting substances. This yields MHA solutions with lower corrosive properties. However, the salt problem remains.
Finally, EP patent 330,521 describes a one-stage hydrolysis process with sulfuric acid which makes do without solvent and in which crystalline ammonium sulfate is obtained as coproduct along with liquid MHA. This goal is achieved in that the reacted saponification mixture is partially neutralized with ammonia so that the ammonium bisulfate produced as well as any free sulfuric acid still present are converted into the neutral ammonium sulfate. Two liquid phases are produced thereby which, for their part, are separated and concentrated by evaporation in order to obtain on the one hand liquid MHA and on the other hand crystalline ammonium sulfate. A suitable combination of the various filtration- and return steps brings it about that no product is lost and the formation of a waste water loaded with salts is avoided. The resulting MHA is of a very good quality. However, in spite of these advantages the process also has significant disadvantages. For the one, the isolated ammonium sulfate has a sticky consistency and is encumbered with an intensive odor, so that the salt must still be purified subsequently e.g. by recrystallization in order to obtain it in saleable form. For the other, the rather dilute procedure in conjunction with the rather high excess of mineral acid necessary thereby results in additional expenses which are reflected in higher supply numbers and a greater energy requirement e.g. in the various concentrating operations. In addition, there is an expensive handling of solids. All these factors render the process considerably more expensive. For the rest, the resulting monomer/oligomer concentrate is subject to the same ageing process as the one obtained according to EP patents 142,488 and 143,100.
The processes of U.S. Pat. Nos. 2,745,745; 2,938,053; 3,175,000; 4,310,690 and GB patents 722,024 and 915,193 are relative to the production of the alkaline/alkaline-earth salts of MHA, especially of the calcium- and mixed calcium ammonium salt. All instances of salt formation in them are preceded by the obtention of the MHA intermediate by mineral-acidic nitrile hydrolysis.
The two-stage hydrolysis with sulfuric acid forms the basis for the processes of U.S. Pat. Nos. 2,745,745; 2,938,053 and 3,175,000. In the first two publications cited the rather dilute saponification mixture is treated with e.g. calcium hydroxide or -carbonate in an amount which is at least sufficient for bonding the sulfate ions. Calcium sulfate is precipitated thereby and ammonia released, which for its part reacts with MHA to the ammonium salt MHAAS. The salt can be obtained from the solution by concentration by evaporation in impure form as viscous oil or hygroscopic solid. However, it can also be reacted preferably by the addition of more calcium hydroxide/carbonate to the calcium- or calcium ammonium salt of MHA, which are obtained in solid form after the concentration by evaporation. The same result is obtained if the saponification solution is treated immediately with a sufficient excess of the basic calcium compound. MHA amide is used as initial product in GB patent 722,024. For the rest, the process for obtaining the MHA salts is identical with the process described above.
In order to avoid the compulsory case of the worthless calcium sulfate coproduct, in U.S. Pat. No. 3,175,000 the sulfuric-acid saponification mixture is compounded with more ammonium sulfate until saturation. As a result of the salting-out effect two phases form, during which over 90% of the MHA is separated out in the organic phase. This MHA can be further processed directly to the calcium salt. The residual MHA is separated from the aqueous phase by solvent extraction, preferably ether, and reacted to the calcium salt either separately or after being united with the main fraction under evaporation of the solvent. No data is furnished about the whereabouts of the coproduced ammonium sulfate.
The process of U.S. Pat. No. 4,310,690 describes a solution of the ammonium salt problem. In it the saponification mixture is neutralized with sodium hydroxide solution under defined conditions after the two-stage hydrolysis with hydrochloric acid to the extent that the ammonium chloride formed is completely decomposed into sodium chloride and ammonia. In the subsequent treatment with stoichiometric amounts of caustic lime the MHA calcium salt is obtained as suspension in a practically saturated sodium chloride solution. After the solid/liquid separation a part of the wash filtrate is returned for the preparation of the caustic lime suspension and a sodium chloride solution with little organic ballast is obtained as waste water. No data is presented here either about the use or the whereabouts of the coproduct ammonia.
Finally, GB patent 915,193 describes a continuous process for obtaining the calcium- or ammonium salt of MHA. The process is based on the one-stage saponification of MMP cyanohydrin with strong, dilute, approximately 20% sulfuric acid in excess. The MHA is extracted with higher-boiling ethers from the saponification mixture continuously drawn off after 10 hours residence time, whereupon the MHA calcium salt precipitates in fine, crystalline form by a subsequent treatment of the extract with calcium hydroxide/carbonate suspensions in water and is separated off. If gaseous ammonia is conducted into the ethereal MHA extract for the formation of salt, MHAAS forms, which is separated in oily form. However, the return of the aqueous, acidic raffinate into the hydrolysis stage provided in the process results in an accumulation of ammonium salts and can not be carried out in the manner indicated. Moreover, the long reaction times damage the product.
In view of the state of the art discussed here, the present invention has the problem of indicating a process for producing ammonium-2-hydroxy-4-(methylthio)-n-butyrate (MHAAS) which avoids or at least noticeably diminishes the previously mentioned disadvantages which accompany both the production and the use of known methionine substitutes. The process should also be progressive, particularly from the standpoint of environmental compatibility, which can be achieved especially by avoiding environmentally harmful waste water or the compulsory accumulation of inorganic ammonium salts. A further goal of the invention is to make available a novel active substance suitable for animal nutrition or an active-substance mixture in liquid and stable form containing this active substance, that is, especially with an ageing tendency with is considerably reduced or eliminated over the state of the art.